Cysteine proteinases containing a highly reactive cysteine residue with a free thiol group at the active site have been known as playing an important role in certain conditions distinguished by aberrant protein turnover such as: muscular dystrophy (Am. J. Pathol. 1986, 122, 193-198; Am. J. Pathol. 1987, 127, 461-466), myocardial infarction (J. Am. Coll. Cardiol. 1983, 2, 681-688), bone resorption (Biochem. J. 1991, 279, 167-274; J. Biol. Chem. 1996, 271, 2126-2132; and Biochem. Biophys. Acta 1992, 1116, 57-66), arthritis (Arthritis Rheumatism 1994, 37, 236-247; and Biochem. Pharmacol. 1992, 44, 1201-1207), cancer metastasis (Cancer Metastasis Rev. 1990, 9, 333-352), pulmonary emphysema (Am. Rev. Respir. Dis. 1975,111, 579-586), septic shock (Immunol. Today 1991, 11, 404-410, Biochemistry 1994, 33, 3934-3940), cerebral ischemia, memory function, Alzheimer and cataract (TIPS 1994, 15, 412-419, Bioorg. Med. Chem. Lett. 1995, 4, 387-392, Proc. Natl. Acad. Sci. USA 1991, 88, 10998-11002), malaria (J. Med. Chem. 1995, 38, 5031-5037), glomerular basement membrane degradation (Biochem. Bioph. Acta 1989, 990, 246-251), bacterial infection (Nature 1989, 337, 385-386), inflammatory diseases (Protein Science 1995, 4, 3-12), parasitic infections (Annu. Rev. Microbiol. 1993, 47 821-853; Parasitol. Today 1990, 6, 270-275), and viral infections (Biochem. 1992, 31, 7862-7869).
A variety of cysteine proteinase have been shown to be present in mammalian tissue. The most notable of these proteinase are the lysosomal cathepsins (cathepsin B, H, S, K and L) and the cytoplasmic Ca.sup.2+ dependent enzymes, the calpains. These enzymes are, therefore, excellent targets for the development of specific inhibitors as possible therapeutic agents.
Cysteine proteinase are inhibited by several types of peptide derived inhibitors such as peptidyl aldehyde (Eur. J. Biochem. 1982, 129, 3341), chloromethyl ketone (Acta. Biol. Med. Ger. 1981, 40, 1503-151 1), diazomethyl ketone (Biochemistry 1977,16, 5857-5861), monofluoromethyl ketone (Biochemical Pharmacology 1992 44,1201-1207), acyloxy methyl ketone (J. Med. Chem. 1994, 37, 1833-1840), O-acyl hydroxamates (Biochem. Biophy. Research Communications 1988, 155, 1201-1206), methyl sulphonium salts (J. Biol. Chem. 1988,263, 2768-2772) and epoxy succinyl derivatives (Agric. Biol. Chem. 1978, 42, 523-527) without significantly inhibiting other classes of proteinases.
Unfortunately, the effectiveness in vivo of such compounds is not as much as expected on the basis of in vitro inhibitory activity, and there exits a continuing need to develop new cysteine proteinase inhibitors with high selectivity and lower toxicity. ##STR2##
Our laboratory has been actively involved in search of novel types of cysteine proteinase inhibitors with high selectivity among cysteine proteinase class of enzymes. We have found that a novel class of compounds having natural peptidyl group at C-3 of reactive group 3-amino-4-substituted azetidin-2-one, represented by formula 1, exhibit an excellent cysteine proteinase regulatory (e.g., inhibitory) activity and selectivity among cysteine proteinases, which is reported in U.S. patent application Ser. No. 08/415,055.